Lesions can form in central nervous system (“CNS”) tissue for a number of reasons. One of the leading causes of CNS lesions is stroke. Stroke is characterized by the sudden loss of circulation to an area of the brain, resulting in a corresponding loss of neurologic function. Also called cerebrovascular accident or stroke syndrome, stroke is a nonspecific term encompassing a heterogeneous group of pathophysiologic causes, including thrombosis, embolism, and hemorrhage. Recent reports indicate an incidence exceeding 500,000 new strokes of all types per year. Stroke is a leading killer and disabler. Combining all types of stroke, it is the third leading cause of death and the first leading cause of disability. At current trends, this number is projected to jump to one million per year by the year 2050. When the direct costs (care and treatment) and the indirect costs (lost productivity) of strokes are considered together, strokes cost US society $43.3 billion per year. Strokes currently are classified as either hemorrhagic or ischemic. Acute ischemic stroke refers to strokes caused by thrombosis or embolism and accounts for 80% of all strokes.
The four major neuroanatomic ischemic stroke syndromes are caused by disruption of their respective cerebrovascular distributions.
Anterior cerebral artery occlusions primarily affect frontal lobe function, producing altered mental status, impaired judgment, contralateral lower extremity weakness and hypesthesia, and gait apraxia.
Middle cerebral artery (MCA) occlusions commonly produce contralateral hemiparesis, contralateral hypesthesia, ipsilateral hemianopsia (blindness in one half of the visual field), and gaze preference toward the side of the lesion. Agnosia is common, and receptive or expressive aphasia may result if the lesion occurs in the dominant hemisphere. Since the MCA supplies the upper extremity motor strip, weakness of the arm and face is usually worse than that of the lower limb.
Posterior cerebral artery occlusions affect vision and thought, producing homonymous hemianopsia, cortical blindness, visual agnosia, altered mental status, and impaired memory.
Vertebrobasilar artery occlusions are notoriously difficult to detect because they cause a wide variety of cranial nerve, cerebellar, and brainstem deficits. These include vertigo, nystagmus, diplopia, visual field deficits, dysphagia, dysarthria, facial hypesthesia, syncope, and ataxia. Loss of pain and temperature sensation occurs on the ipsilateral face and contralateral body. In contrast, anterior strokes produce findings on one side of the body only.
These occlusions may occur for a variety of reasons. Emboli may arise from the heart, the extracranial arteries or, rarely, the right-sided circulation (paradoxical emboli). The sources of cardiogenic emboli include valvular thrombi (e.g., in mitral stenosis, endocarditis, prosthetic valves); mural thrombi (e.g., in myocardial infarction [MI], atrial fibrillation, dilated cardiomyopathy); and atrial myxomas. MI is associated with a 2-3% incidence of embolic stroke, of which 85% occur in the first month after MI.
Lacunar infarcts account for 13-20% of all cerebral infarctions and usually involve the small terminal vasculature of the subcortical cerebrum and brainstem. Lacunar infarcts commonly occur in patients with small vessel disease, such as diabetes and hypertension. Small emboli or an in situ process called lipohyalinosis is thought to cause lacunar infarcts. The most common lacunar syndromes include pure motor, pure sensory, and ataxic hemiparetic strokes. By virtue of their small size and well-defined subcortical location, lacunar infarcts do not lead to impairments in cognition, memory, speech, or level of consciousness.
The most common sites of thrombotic occlusion are cerebral artery branch points, especially in the distribution of the internal carotid artery. Arterial stenosis (i.e., turbulent blood flow), atherosclerosis (i.e., ulcerated plaques), and platelet adherence cause the formation of blood clots that either embolize or occlude the artery. Less common causes of thrombosis include polycythemia, sickle cell anemia, protein C deficiency, fibromuscular dysplasia of the cerebral arteries, and prolonged vasoconstriction from migraine headache disorders. Any process that causes dissection of the cerebral arteries also can cause thrombotic stroke (e.g., trauma, thoracic aortic dissection, arteritis). Occasionally, hypoperfusion distal to a stenotic or occluded artery or hypoperfusion of a vulnerable watershed region between two cerebral arterial territories can cause ischemic stroke.
Turning to hemorrhagic stroke, the terms intracerebral hemorrhage (ICH) and hemorrhagic stroke are used interchangeably in this discussion and are regarded as a separate entity from hemorrhagic transformation of ischemic stroke. ICH accounts for approximately 20% of all strokes and is associated with higher mortality rates than cerebral infarctions. Patients with hemorrhagic stroke present with similar focal neurologic deficits but tend to be more ill than patients with ischemic stroke. Patients with intracerebral bleeds are more likely to have headache, altered mental status, seizures, nausea and vomiting, and/or marked hypertension; however, none of these findings distinguish reliably between hemorrhagic and ischemic strokes.
In ICH, bleeding occurs directly into the brain parenchyma. The usual mechanism is thought to be leakage from small intracerebral arteries damaged by chronic hypertension. Other mechanisms include bleeding diatheses, iatrogenic anticoagulation, cerebral amyloidosis, and cocaine abuse. ICH tends to be found in certain sites in the brain, including the thalamus, putamen, cerebellum, and brain stem. In addition to the area of the brain injured by the hemorrhage, the surrounding brain can be damaged by pressure produced by the mass effect of the hematoma. A general increase in intracranial pressure may occur. The 30-day mortality rate for hemorrhagic stroke is 40-80%. Approximately 50% of all deaths occur within the first 48 hours.
Other causes for CNS lesions are conventionally known, including trauma and various diseases of the CNS.
Treating CNS lesions implicates neurogenesis, i.e. the (re)generation of neurons in a region of a patient's tissue that is of interest, including but not limited to replacement of damaged neurons in a central nervous system lesion. Unfortunately, neuronal (CNS) tissue is well-known for its limited reparative/regenerative capacity. The generation of new neurons in the adult is largely restricted to two regions, the SVZ lining the lateral ventricles, and the subgranular zone of the dentate gyrus. Limited neuronal replacement has been demonstrated resulting from endogenous precursor stem cells that had migrated from the SVZ.
Some initial success has been reported with certain neurogenesis methods but these methods have not been clinically successful. Accordingly, what is needed are methods and compositions that overcome problems noted in the art for treatment of central nervous system lesions.